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To investigate the different effects of isocaloric high-fat diet (HFD) and high-carbohydrate diet (HCD) on hepatic steatosis and the underlying mechanisms, especially the role of microRNA-34a/silent information regulator T1 (SIRT1) axis, C57BL/6J mice (n = 12/group) were isocaloric pair-fed with Lieber-DeCarli liquid diet containing either high fat (HFLD) or high carbohydrate (HCLD) for 16 weeks. As compared to the HFLD fed mice, despite the similar final body weights, HCLD feeding: (1) induced more severe hepatic steatosis; (2) up-regulated hepatic expression of miR-34a accompanied with significant decrease of SIRT1 and nicotinamide phosphoribosyltransferase (NAMPT), SIRT1 activity and phosphorylation of AMPK; (3) up-regulated  de novo  lipogenesis (DNL) related proteins expression (ACC, SCD1), and down-regulated expressions of miR-122, miR-370 and miR-33; (4) decreased mRNA expressions of genes  Cpt1, Pparα and Pgc1α  related to fatty acid oxidation; (5) increased hepatic total cholesterol concentration and decreased expression of cholesterol metabolism related genes  Abcg5, Abcg8, Abcg11, Cyp7a1  and  Cyp8b1 ; and (6) induced higher hepatic inflammatory response accompanied with significant increased mRNA expressions of  Il1β ,  Tnfα  and  Mcp1 . Thus, isocaloric HCLD feeding induced greater severity in hepatic steatosis and inflammatory response than HFLD feeding, potentially through miR-34a/SIRT1 axis mediated promotion of DNL, inhibition of fatty acid oxidation and cholesterol metabolism.

Isocaloric Pair-Fed High-Carbohydrate Diet Induced More Hepatic Steatosis and Inflammation than High-Fat Diet Mediated by miR-34a/SIRT1 Axis in Mice